Two experimental goals of the original award were to determine if pulmonary stretch reflexes and/or systemic O2 levels modulate sympathetic (vasoconstrictor) nerve activity to skeletal muscle (MSNA) under resting conditions and during acute exercise in healthy humans. The findings to date indicate that: 1) vagal lung inflation feedback mediates most of the within- breath variation in MSNA observed at rest; 2) sustained, but not brief, systemic hypoxia stimulates MSNA at rest and potentiates the response to forearm muscle contractions; and 3) even brief systemic hyperoxia inhibits MSNA under resting conditions, but has no obvious effect on the response to forearm contractions. This renewal application proposes to extend these findings by determining: a) if vagal lung inflation reflexes inhibit the increase in total minute MSNA during more conventional (i.e., large-muscle) dynamic exercise; b) if respiratory-related (within-breath) variation in vasoconstrictor and/or sudomotor skin sympathetic nerve activity (SSNA) is observed under resting conditions, and whether vagal lung inflation feedback modulates SSNA at rest or during acute exercise: c) if peripheral chemoreceptors mediate the systemic O2 influence on MSNA at rest, and the mechanisms underlying the potential O2 modulatory effects on MSNA during large- muscle, dynamic exercise; and d) if systemic O2 levels influence vasoconstrictor and/or sudomotor SSNA at rest and during exercise, and if so, the nature of the underlying mechanisms. The target tissue effects of respiratory-linked changes in nerve activity will also be established. It is hypothesized that both phasic pulmonary vagal feedback and peripheral chemoreflexes exert physiologically significant modulatory influences on MSNA and SSNA at rest and during dynamic exercise. Moreover, it is postulated that, as in anesthetized animals, vasoconstrictor SSNA is regulated in an antagonistic manner to both MSNA and sudomotor SSNA in the conscious human. To test these concepts, continuous recordings of sympathetic nerve activity (via microneurography), arterial blood pressure, heart rate, breathing frequency and volume, end-tidal O2 and CO2, whole limb and skin blood flow, and skin electrical conductance (index of sweat gland activity) will be made at rest and during cycling exercise while tidal volume or systemic O2 levels (and end-tidal CO2) are manipulated under rigorously controlled laboratory conditions. Vasoconstrictor and sudomotor SSNA will be examined selectively by changing the ambient temperature. Studies will be performed primarily in normal human subjects; however the role of vagal lung inflation feedback will also be investigated in experiments on denervated lung transplant patients. Both within-breath and steady-state analyses will be performed on all variables. The proposed studies will provide substantial new information on respiratory modulation of sympathetic nerve activity in conscious humans. Such data should enhance our understanding of autonomic circulatory control in both physiological (e.g., altitude) and pathophysiological (e.g., cardiopulmonary disease) states.